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1.
Braz. j. biol ; 83: e243910, 2023. tab, graf
Article in English | LILACS, VETINDEX | ID: biblio-1278525

ABSTRACT

Abstract Nucleotide excision repair (NER) acts repairing damages in DNA, such as lesions caused by cisplatin. Xeroderma Pigmentosum complementation group C (XPC) protein is involved in recognition of global genome DNA damages during NER (GG-NER) and it has been studied in different organisms due to its importance in other cellular processes. In this work, we studied NER proteins in Trypanosoma cruzi and Trypanosoma evansi, parasites of humans and animals respectively. We performed three-dimensional models of XPC proteins from T. cruzi and T. evansi and observed few structural differences between these proteins. In our tests, insertion of XPC gene from T. evansi (TevXPC) in T. cruzi resulted in slower cell growth under normal conditions. After cisplatin treatment, T. cruzi overexpressing its own XPC gene (TcXPC) was able to recover cell division rates faster than T. cruzi expressing TevXPC gene. Based on these tests, it is suggested that TevXPC (being an exogenous protein in T. cruzi) interferes negatively in cellular processes where TcXPC (the endogenous protein) is involved. This probably occurred due interaction of TevXPC with some endogenous molecules or proteins from T.cruzi but incapacity of interaction with others. This reinforces the importance of correctly XPC functioning within the cell.


Resumo O reparo por excisão de nucleotídeos (NER) atua reparando danos no DNA, como lesões causadas por cisplatina. A proteína Xeroderma Pigmentosum complementation group C (XPC) está envolvida no reconhecimento de danos pela via de reparação global do genoma pelo NER (GG-NER) e tem sido estudada em diferentes organismos devido à sua importância em outros processos celulares. Neste trabalho, estudamos proteínas do NER em Trypanosoma cruzi e Trypanosoma evansi, parasitos de humanos e animais, respectivamente. Modelos tridimensionais das proteínas XPC de T. cruzi e T. evansi foram feitos e observou-se poucas diferenças estruturais entre estas proteínas. Durante testes, a inserção do gene XPC de T. evansi (TevXPC) em T. cruzi resultou em crescimento celular mais lento em condições normais. Após o tratamento com cisplatina, T. cruzi superexpressando seu próprio gene XPC (TcXPC) foi capaz de recuperar as taxas de divisão celular mais rapidamente do que T. cruzi expressando o gene TevXPC. Com base nesses testes, sugere-se que TevXPC (sendo uma proteína exógena em T. cruzi) interfere negativamente nos processos celulares em que TcXPC (a proteína endógena) está envolvida. Isso provavelmente ocorreu pois TevXPC é capaz de interagir com algumas moléculas ou proteínas endógenas de T.cruzi, mas é incapaz de interagir com outras. Isso reforça a importância do correto funcionamento de XPC dentro da célula.


Subject(s)
Humans , Animals , Trypanosoma cruzi/genetics , Xeroderma Pigmentosum , DNA Damage/genetics , Computational Biology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , DNA Repair/genetics
2.
São Paulo; s.n; 2020. 99 p. figuras, tabelas.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1102465

ABSTRACT

A síndrome do Xeroderma Pigmentoso (XP) ocorre frente à herança monogênica e bialélica de variantes germinativas patogênicas de perda ou redução de função em genes das vias de reparo por excisão de nucleotídeos ou síntese translesão. Consequentemente, é estabelecida deficiência na correção de lesões induzidas, principalmente por radiação ultravioleta, favorecendo alta sensibilidade à radiação solar e risco aumentado para o desenvolvimento de múltiplas lesões cutâneas pré-malignas e malignas. Visto que a heterogeneidade na manifestação clínica da síndrome é uma questão em discussão na literatura, para investigar este aspecto propusemos avaliar o perfil de variantes germinativas e variantes somáticas de tumores cutâneos e não cutâneos de indivíduos portadores de XP. Foi realizado o sequenciamento de alto desempenho utilizando a plataforma NextSeq (Illumina) para avaliar as regiões codificantes de 114 genes selecionados pela sua relevância em desordens dermatológicas, tumorigênese e fisiologia cutânea e resposta de dano ao DNA. Seis pacientes com fenótipo clínico da síndrome do XP e portadores de variantes germinativas clinicamente relevantes nos genes XPC ou POLH/XPV foram avaliados no estudo. Variantes germinativas de significado incerto foram identificadas, em heterozigose, no DNA de leucócito de cinco dos seis pacientes avaliados ocorrendo nos genes DNAH11, PCDHB3, RGS22, SLC27A5, TTN e UGT2B10 e nenhuma das variantes identificadas apresentou perda de heterozigose do alelo selvagem nos tecidos tumorais. O polimorfismo de risco para carcinoma basocelular de pele (CBC) rs3769823[A] no gene CASP8 não foi identificado em apenas um caso do estudo, o qual desenvolveu o menor número de tumores. O polimorfismo de risco rs1126809[A] no gene TYR foi detectado apenas no caso que apresentou o maior número de CBC. Amostras de DNA de nove CBCs de tecido armazenado em parafina e duas amostras de tumor gástrico de uma mesma peça cirúrgica, de tecido armazenado em parafina e congelado a fresco, foram avaliadas de forma pareada com o DNA de leucócito correspondente, para pesquisa de variantes somáticas. Variantes somáticas não foram identificadas na amostra de CBC da paciente XP-C com fenótipo menos agressivo da síndrome. O total de 235 variantes missense e 29 variantes de perda de função foram identificadas em 71 genes para sete amostras de CBC, mínimo de 11 e máximo de 127 variantes por amostra, com 85,2% destas apresentando frequência alélica ≥20%. Com exceção de um CBC, mais de 95% das variantes somáticas identificadas representam alterações tipicamente fotoinduzidas (C:G>T:A e G:C>T:A). Embora pacientes XP acumulem maior número de mutações devido deficiência no mecanismo de reparo, não observamos carga mutacional diferente do observado em CBCs esporádicos. Vinte e sete genes apresentaram variantes somáticas em mais de uma amostra de CBC. Nenhum gene foi compartilhado entre as sete amostras de CBC. Entre os genes alterados em maior número de tumores estão incluídos genes drivers de CBC (LATS1, NOTCH2, PTCH1, PTPN14 e TP53), bem como genes não clássicos na carcinogênese do CBC (APC, FLG e TTN). Uma variante driver em SMO foi recorrente em três CBCs de um mesmo paciente. Duas variantes somáticas foram identificadas no tumor gástrico de tecido congelado a fresco ocorrendo nos genes GLI3 e RB1, não sendo as mesmas detectadas no tecido armazenado em parafina. Nesse trabalho, ressalta-se a heterogeneidade na manifestação clínica da síndrome do XP e a identificação de dois polimorfismos de risco, bem como destaca-se o papel central das vias Sonic Hedgehog e Hippo na carcinogênese do CBC de pacientes XP (AU)


The Xeroderma Pigmentosum (XP) syndrome occurs on base of biallelic inheritance of pathogenic germline variants of loss of function or function reduction in genes that plays role in nucleotide excision repair and translesion synthesis. Consequently, patients are deficient in correct DNA lesions mainly induced by ultraviolet radiation, present high sensitivity to solar radiation and increased risk for the development of multiple premalignant and malignant skin lesions. Since the heterogeneity in the clinical manifestation is under constantly discussion in the literature, to investigate it we proposed to explore the profile of germline variants and somatic variants in skin and non-skin tumors from XP patients. High-performance sequencing using the NextSeq (Illumina) platform was performed to assess the coding regions of 114 genes selected for their relevance in dermatological disorders, skin carcinogenesis, cutaneous physiology and DNA damage response. Six patients with clinical phenotype of XP syndrome and carriers of clinically relevant germline variants in the XPC or POLH/XPV genes were evaluated in the study. Heterozygous germline variants of uncertain significance were identified in the leukocyte DNA from five of the six patients occurring in DNAH11, PCDHB3, RGS22, SLC27A5, TTN and UGT2B10 genes. None of the identified variants showed loss of heterozygosity of the wild allele in tumor tissues. The CASP8 risk polymorphism for basal cell carcinoma of the skin (BCC) rs3769823[A] was not identified in only one case of the study which developed the minor number of tumors. The TYR risk polymorphism rs1126809[A] was detected only in the case with the highest number of BCC. Somatic variants were investigated in DNA from nine samples of BCCs (tissue stored in paraffin) and two samples of gastric tumor from the same surgical (tissue stored in paraffin and fresh frozen), all paired with the corresponding leukocyte DNA. Somatic variants were not identified in the BCC sample of XP-C patient with a less aggressive syndrome phenotype. A total of 235 missense variants and 29 loss of function variants were identified in 71 genes for seven BCC samples. A minimum of 11 and a maximum of 127 variants per sample were detected, with 85.2% showing an allelic frequency ≥20%. Except for one BCC, more than 95% of the identified somatic variants represented typically photoinduced mutations (C:G>T:A and G:C>T:A). Although XP patients accumulate a greater number of mutations due to deficiency in the repair mechanism, we did not observe different mutational load compared with sporadic BCCs. Twenty-seven genes showed somatic variants in more than one BCC sample. Genes shared between the seven BCC samples were not found. Among the altered genes in a greater number of tumors, it was identified BCC driver genes (LATS1, NOTCH2, PTCH1, PTPN14 and TP53), as well as genes non-classical for BCC carcinogenesis (APC, FLG and TTN). A driver variant in SMO was recurrent in three BCCs from the same patient. Two somatic variants in GLI3 and RB1 genes were identified occurring only in the fresh frozen tissue of gastric tumor, not in the tissue stored in paraffin. In this work, the heterogeneous clinical manifestation of XP syndrome is highlighted, as well as the identification of two risk polymorphisms. In addition, this work emphasizes the central role of the Sonic Hedgehog and Hippo pathways in BCC carcinogenesis of XP patients.


Subject(s)
Humans , Male , Middle Aged , Skin Neoplasms , Stomach Neoplasms , Xeroderma Pigmentosum , Carcinoma, Basal Cell , DNA Repair , High-Throughput Nucleotide Sequencing , Ultraviolet Rays
3.
Mali méd. (En ligne) ; 34(3): 44-46, 2019. ilus
Article in French | AIM | ID: biblio-1265752

ABSTRACT

Le Xéroderma pigmentosum (XP) est lié à un défaut des enzymes impliquées dans la réparation des effets oncogènes de l'exposition aux ultraviolets. L'affection se rencontre dans le monde entier, dans toutes les ethnies et races. Cette génodermatose rare est souvent méconnue dans les pays en manque de spécialiste en dermatologie. Cette rareté de Xeroderma pigmentosum et l'insuffisance de personnel qualifié engendrent des difficultés diagnostiques de cette pathologie surtout en Afrique Occidentale où le XP est diagnostiqué à tort pour d'autres pathologies. Objectif: Partager avec les confrères la problématique de diagnostic de Xéroderma pigmentosum dans les pays en insuffisance de dermatologues et de plateau technique. Observation: il s'agissait d'un patient de 21 ans, sexe masculin, sans antécédents pathologique de dermatoses, issu d'un mariage consanguin qui a consulté pour sècheresse cutanée et photophobie après un long parcours dans beaucoup des centres de santé de la place sans diagnostic et sans amélioration notable, chez qui l'interrogatoire a retrouvé la notion de consanguinité (son père et sa mère sont des cousins, et provenaient du même clan Dogon),l'absence de troubles pigmentaires cutanées à la naissance et l'apparition des troubles pigmentaires cutanées à l'âge de 16ans. L'examen physique a objectivé la photophobie en plus des signes cliniques et paracliniques specifiques ce qui a permis de retenir le diagnostic de Xéroderma pigmentosum, forme variante. Conclusion: en Afrique Occidentale, la difficulté diagnostique de Xéroderma pigmentosum est sans doute en rapport avec un manque de personnel qualifié et des moyens techniques de diagnostic, ce qui rend sa fréquence sous-estimée


Subject(s)
Africa, Western , Mali , Xeroderma Pigmentosum
4.
Article in Korean | WPRIM | ID: wpr-738617

ABSTRACT

PURPOSE: To discuss the clinical course and diagnosis of corneal dysplasia in a xeroderma pigmentosum patient based on a genetic evaluation. CASE SUMMARY: A 42-year-old female visited our clinic for decreased left visual acuity and corneal opacity. She had undergone several surgeries previously due to the presence of basosquamous carcinoma in the left lower eyelid, neurofibroma, and malignant melanoma of the facial skin. The patient showed repeated corneal surface problems, with a suspicious dendritic lesion; however, antiviral therapy was ineffective, and herpes simplex virus polymerase chain reaction results were negative. Despite regular follow-ups, the patient showed neovascularization around the corneal limbus and an irregular corneal surface. We performed corneal debridement with autologous serum eye drops for treatment. The patient's visual acuity and corneal surface improved after the procedure. The impression cytology result was corneal dysplasia. In whole exome sequencing, two pathogenic variants and one likely pathogenic variant of the POLH gene were detected. CONCLUSIONS: This is the first genetically identified xeroderma pigmentosum case with ophthalmological lesions of the eyelid and cornea in Korea. Debridement of the irregular corneal surface and autologous serum eye drop administration in xeroderma pigmentosum could be helpful for improving visual acuity.


Subject(s)
Adult , Carcinoma, Basosquamous , Cornea , Corneal Opacity , Debridement , Diagnosis , Exome , Eyelids , Female , Follow-Up Studies , Humans , Ichthyosis , Korea , Limbus Corneae , Melanoma , Neurofibroma , Ophthalmic Solutions , Polymerase Chain Reaction , Simplexvirus , Skin , Visual Acuity , Xeroderma Pigmentosum
5.
São Paulo; s.n; s.n; 2018. 112 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-967941

ABSTRACT

A ausência de XPC, uma proteína canonicamente envolvida em reparo de DNA por excisão de nucleotídeos, está associada a vários fenótipos característicos de disfunção mitocondrial como o desequilíbrio entre os complexos da cadeia transportadora de elétrons (CTE), redução no consumo de oxigênio, maior produção de peróxido de hidrogênio, e maior sensibilidade a agentes que causam estresse mitocondrial. Contudo, uma descrição mecanística da relação entre deficiência de XPC e disfunção mitocondrial ainda não está bem estabelecida. Aqui mostramos que a deficiência de XPC está associada ao aumento na expressão do supressor de tumor p53. Essa alteração é acompanhada pelo aumento da expressão de diversas proteínas que participam em importantes funções mitocondriais. A inibição de p53 reverte a superexpressão de algumas dessas proteínas. O tratamento com o inibidor do Complexo III da CTE antimicina A induz aumento da expressão de p53 de forma mais acentuada na linhagem Xpc-/-, enquanto o tratamento com o antioxidante N-acetilcisteína diminue a produção basal de H2O2, expressão de p53 e sensibilidade aumentada ao tratamento com antimicina A. Em conjunto, nossos resultados suportam a hipótese de que o aumento da produção de H2O2 em células Xpc-/- tem um papel causal na regulação da expressão de p53 e na disfunção mitocondrial


Although XPC has been initially implicated in the nucleotide excision DNA repair pathway, its deficiency is associated with mitochondrial dysfunction, including unbalanced electron transport chain (ETC) activity, lower oxygen consumption, increased hydrogen peroxide production, and greater sensitivity to mitochondrial stress. However, a mechanistic understanding of the role of XPC in regulating mitochondrial function is still not well established. Here we show that XPC deficiency is associated with increased expression of the tumor suppressor p53, which is accompanied by increased expression of several proteins that participate in important mitochondrial functions. Inhibition of p53 reverses the overexpression of some of these proteins. In addition, treatment with the ETC inhibitor antimycin A induces p53 expression more robustly in the Xpc-/- cells, while treatment with the antioxidant N-acetylcysteine decreases basal H2O2 production, p53 expression and sensitivity to antimycin A treatment. Together, our results support a model in which increased H2O2 production in Xpc-/- causes upregulation of p53 expression and mitochondrial dysfunction


Subject(s)
Xeroderma Pigmentosum/classification , Tumor Suppressor Protein p53/pharmacokinetics , Mitochondrial Proteins , Hydrogen Peroxide/analysis , Genes, p53/physiology , Antimycin A/adverse effects
6.
Rev. bras. oftalmol ; 76(4): 202-206, July-Aug. 2017. tab, graf
Article in Portuguese | LILACS | ID: biblio-899070

ABSTRACT

Resumo Relato de um caso clínico de Xeroderma Pigmentoso com carcinoma espinocelular de conjuntiva bilateral que apresentou regressão importante das dimensões tumorais com o uso de Interferon alfa-2b tópico. Relato de caso: Paciente feminina com Xeroderma Pigmentoso em estágio avançado, com ausência de pele sadia, tendo sido submetida a cerca de 60 exéreses de lesões de pele malignas. A paciente compareceu com tumoração conjuntival em ambos os olhos, correspondendo a carcinoma espinocelular de conjuntiva e neoplasia intraepitelial de conjuntiva em olho esquerdo. Devido as dificuldades cirúrgicas, alta taxa de recidiva e elevada probabilidade de formação de simbléfaro foi-se iniciado terapêutica com Interferon alfa-2beta 1.000.000 unidades tópico, obtendo-se bons resultados com importante regressão do tamanho da lesão e resolução dos sintomas. Conclusão: O uso tópico de interferon alfa-2beta em neoplasia escamosa de conjuntiva, mostrou-se uma boa opção terapêutica em situações de elevado risco cirúrgico e de complicações pós operatórias.


Abstract Report of a case of xeroderma pigmentosum with squamous cell carcinoma of bilateral conjunctiva that showed a significant regression in tumor size with the use of interferon alfa-2b topic. Case report: Female patient with Xeroderma pigmentosum in an advanced stage, with no healthy skin, having been subjected to about 60 excisions of malignant skin lesions. The patient appeared with conjunctival tumors in both eyes, corresponding to squamous cell carcinoma of the conjunctiva. Due to surgical difficulties, high relapse rate and high probability of symblepharon formation, therapy was started with interferon alpha 2beta 1,000,000 topic units, obtaining good results with a significant decrease in lesion size and resolution of symptoms. Conclusion: Topical use of alpha-interferon in 2beta squamous neoplasia of the conjunctiva proved to be a good therapeutic option for high surgical risk and situations of postoperative complications.


Subject(s)
Humans , Female , Adult , Xeroderma Pigmentosum/complications , Carcinoma in Situ , Carcinoma, Squamous Cell , Conjunctival Neoplasms/diagnosis , Conjunctival Neoplasms/pathology , Conjunctival Neoplasms/drug therapy , Administration, Ophthalmic , Interferon alpha-2/therapeutic use
7.
Article in English | WPRIM | ID: wpr-633445

ABSTRACT

BACKGROUND: Non-melanoma skin cancers (NMSC) consists of  basal-cell carcinomas (BCC) and squamous-cell carcinomas (SCC).Certain populations are predisposed to develop  NMSC,  including  patients  with  previous  history  of  NMSC.Systemic  retinoids  have  shown  promising  results  in chemoprevention of recurrence of NMSC in other high-risk populations (xeroderma pigmentosum and renal-transplant patients).We  assessed  the  efficacy  and  safety  of  low-dose  systemic  retinoids  compared  with  placebo,  as  a  chemopreventive agent for NMSC in patients with previous NMSC.METHODOLOGY: Electronic  databases  were  systematically searched for this study. Participants in the studies selected must have had a biopsy-proven NMSC, over 18 years of age, with  no  exclusion  of  other  demographic  characteristics. All  types  of  systemic  retinoids  were  included  with  no restriction on dosage. Two authors independently performed standardized  eligibility  assessment  and  data-extraction.Differences in opinion were resolved by consensus with the third author. Statistical analysis was done using the Review Manager 5 software.RESULTS: Eleven full-text studies were assessed for eligibility out of 178 studies found. Five studies were excluded because of the different population, while the two articles used topical retinoids. Four articles were included. The interventions were 10.0 mg isotretinoin, 25,000IU retinol and 25.0 mg acitretin,compared with placebo. Meta-analysis produced RR of 0.94 (95% CI, 0.89-1.00), with moderate heterogeneity (34%) due to the difference in interventions used. There are significantly more  adverse  events  in  the  retinoids  group,  especially  in the  incidence  of  mucocutaneous  adverse  events,  and deranged lipid profile and liver enzymes.CONCLUSION: There is insufficient evidence to support the use of low-dose systemic retinoids as chemoprevention for patients with previous NMSC. Furthermore, adverse events may limit their use. Topical preparations with less side-effects may be investigated.


Subject(s)
Humans , Male , Female , Aged , Middle Aged , Adult , Vitamin A , Acitretin , Xeroderma Pigmentosum , Kidney Transplantation , Carcinoma, Basal Cell , Carcinoma, Squamous Cell
8.
Article in English | WPRIM | ID: wpr-135154

ABSTRACT

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by xerosis, ultraviolet light sensitivity, and cutaneous dyspigmentation. Due to defects in their DNA repair mechanism, genetic mutations and carcinogenesis inevitably occurs in almost all patients. In these patients, reconstruction of cutaneous malignancies in the head and neck area is associated with some challenges such as likelihood of recurrence and an aggressive clinical course. The aim of this study is to discuss the therapeutic options and challenges commonly seen during the course of treatment. METHODS: Between 2005 and 2015, 11 XP patients with head and neck cutaneous malignancies were included in this study. Demographic data and treatment options of the patients were evaluated. RESULTS: The mean age of the patients was 32 years (range, 10-43) (4 males, 7 females). The most common tumor type and location were squamous cell carcinoma (6 patients) and the orbital region (4 patients), respectively. Free tissue transfer was the most commonly performed surgical intervention (4 patients). The average number of surgical procedures was 5.5 (range, 1-25). Six patients were siblings with each other, 5 patients had local recurrences, and one patient was lost to follow-up. CONCLUSIONS: Although genetic components of the disease have been elucidated, there is no definitive treatment algorithm. Early surgical intervention and close follow-up are the gold standard modalities due to the tendency toward rapid tumor growth and possible recurrence. Treatment must be individualized for each patient. In addition, the psychological aspect of the disease is an important issue for both patients and families.


Subject(s)
Carcinogenesis , Carcinoma, Squamous Cell , DNA Repair , Follow-Up Studies , Free Tissue Flaps , Head and Neck Neoplasms , Head , Humans , Ichthyosis , Lost to Follow-Up , Male , Neck , Orbit , Recurrence , Siblings , Skin Neoplasms , Ultraviolet Rays , Xeroderma Pigmentosum
9.
Article in English | WPRIM | ID: wpr-135152

ABSTRACT

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by xerosis, ultraviolet light sensitivity, and cutaneous dyspigmentation. Due to defects in their DNA repair mechanism, genetic mutations and carcinogenesis inevitably occurs in almost all patients. In these patients, reconstruction of cutaneous malignancies in the head and neck area is associated with some challenges such as likelihood of recurrence and an aggressive clinical course. The aim of this study is to discuss the therapeutic options and challenges commonly seen during the course of treatment. METHODS: Between 2005 and 2015, 11 XP patients with head and neck cutaneous malignancies were included in this study. Demographic data and treatment options of the patients were evaluated. RESULTS: The mean age of the patients was 32 years (range, 10-43) (4 males, 7 females). The most common tumor type and location were squamous cell carcinoma (6 patients) and the orbital region (4 patients), respectively. Free tissue transfer was the most commonly performed surgical intervention (4 patients). The average number of surgical procedures was 5.5 (range, 1-25). Six patients were siblings with each other, 5 patients had local recurrences, and one patient was lost to follow-up. CONCLUSIONS: Although genetic components of the disease have been elucidated, there is no definitive treatment algorithm. Early surgical intervention and close follow-up are the gold standard modalities due to the tendency toward rapid tumor growth and possible recurrence. Treatment must be individualized for each patient. In addition, the psychological aspect of the disease is an important issue for both patients and families.


Subject(s)
Carcinogenesis , Carcinoma, Squamous Cell , DNA Repair , Follow-Up Studies , Free Tissue Flaps , Head and Neck Neoplasms , Head , Humans , Ichthyosis , Lost to Follow-Up , Male , Neck , Orbit , Recurrence , Siblings , Skin Neoplasms , Ultraviolet Rays , Xeroderma Pigmentosum
10.
Article in English | WPRIM | ID: wpr-164786

ABSTRACT

PURPOSE: Xeroderma pigmentosum (XP) is rare autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet light is deficient. We reported the first molecularly confirmed Korean patient of XP by targeted exome sequencing. The prevalence of XP included all subtype and carrier frequency of XP-A the using public data were estimated for the first time in South Korea. MATERIALS AND METHODS: We described a 4-year-old Korean girl with clinical diagnosis of XP. We performed targeted exome sequencing in the patient for genetic confirmation considering disease genetic heterogeneity and for differential diagnosis. We verified a carrier frequency of c.390-1G>C in XPA gene known as mutational hot spot using Korean Reference Genome Data Base. We estimated the period prevalence of all subtypes of XP based on claims data of the Health Insurance Review and Assessment Service in South Korea. RESULTS: We identified homozygous splicing mutation of XPA (c.390-1G>C) in the patient. The carrier frequency of risk for XPA (c.390-1G>C) was relatively high 1.608 e-03 (allele count 2/1244). The prevalence of XP in South Korea was 0.3 per million people. CONCLUSION: We expect that c.390-1G>C is hot spot for the mutation of XPA and possible founder variant in South Korea. However, the prevalence in South Korea was extremely low compared with Western countries and Japan.


Subject(s)
Child, Preschool , Diagnosis , Diagnosis, Differential , DNA Repair , Exome , Female , Genetic Heterogeneity , Genome , Heredodegenerative Disorders, Nervous System , High-Throughput Nucleotide Sequencing , Humans , Ichthyosis , Insurance, Health , Japan , Korea , Prevalence , Ultraviolet Rays , Xeroderma Pigmentosum
11.
Article in Chinese | WPRIM | ID: wpr-345374

ABSTRACT

Ultraviolet light(UV)-sensitive disorders refer to a group of diseases due to damages to the nucleotide excision repair mechanism which cannot effectively repair DNA damage caused by ultraviolet radiation. The inheritance pattern of such diseases, mainly including xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, is autosomal recessive and known to involve 13 genes. As proteins encoded by such genes are involved in DNA repair and transcription pathways. There is overlap between the symptoms of such diseases, and their genotype - phenotype correlations are quite complex. To facilitate genetic and prenatal diagnosis for such diseases, a summary of the research progress is provided, which mainly focused on mutation research and genotype - phenotype correlation studies. We also propose a strategy for their genetic diagnosis based on recent findings of our group.


Subject(s)
Biomedical Research , Methods , Cockayne Syndrome , Genetics , DNA Damage , DNA Repair , Genetics , Genetic Predisposition to Disease , Genetics , Humans , Skin , Metabolism , Pathology , Radiation Effects , Trichothiodystrophy Syndromes , Genetics , Ultraviolet Rays , Xeroderma Pigmentosum , Genetics
13.
Annals of Dermatology ; : 740-748, 2016.
Article in English | WPRIM | ID: wpr-25361

ABSTRACT

BACKGROUND: Approximately 90%~99% of ultraviolet A (UVA) ray reaches the Earth's surface. The deeply penetrating UVA rays induce the formation of reactive oxygen species (ROS), which results in oxidative stress such as photoproducts, senescence, and cell death. Thus, UVA is considered a primary factor that promotes skin aging. OBJECTIVE: Researchers investigated whether pretreatment with ferulic acid protects human dermal fibroblasts (HDFs) against UVA-induced cell damages. METHODS: HDF proliferation was analyzed using the water-soluble tetrazolium salt assay. Cell cycle distribution and intracellular ROS levels were assessed by flow cytometric analysis. Senescence was evaluated using a senescence-associated β-galactosidase assay, while Gadd45α promoter activity was analyzed through a luciferase assay. The expression levels of superoxide dismutase 1 (SOD1), catalase (CAT), xeroderma pigmentosum complementation group A and C, matrix metalloproteinase 1 and 3, as well as p21 and p16 were measured using quantitative real-time polymerase chain reaction. RESULTS: Inhibition of proliferation and cell cycle arrest were detected in cells that were irradiated with UVA only. Pretreatment with ferulic acid significantly increased the proliferation and cell cycle progression in HDFs. Moreover, ferulic acid pretreatment produced antioxidant effects such as reduced DCF intensity, and affected SOD1 and CAT mRNA expression. These effects were also demonstrated in the analysis of cell senescence, promoter activity, expression of senescent markers, and DNA repair. CONCLUSION: These results demonstrate that ferulic acid exerts protective effects on UVA-induced cell damages via anti-oxidant and stress-inducible cellular mechanisms in HDFs.


Subject(s)
Aging , Animals , Antioxidants , Catalase , Cats , Cellular Senescence , Cell Cycle , Cell Cycle Checkpoints , Cell Death , Complement System Proteins , DNA Repair , Fibroblasts , Humans , Luciferases , Matrix Metalloproteinase 1 , Oxidative Stress , Reactive Oxygen Species , Real-Time Polymerase Chain Reaction , RNA, Messenger , Skin Aging , Superoxide Dismutase , Ultraviolet Rays , Xeroderma Pigmentosum
14.
Protein & Cell ; (12): 210-221, 2016.
Article in English | WPRIM | ID: wpr-757146

ABSTRACT

Xeroderma pigmentosum (XP) is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patient-specific induced pluripotent stem cells (iPSCs) harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells (NSCs) or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clarify the molecular mechanisms of neurological abnormalities in the XP patients.


Subject(s)
DNA Damage , DNA Repair , DNA-Binding Proteins , Genetics , Metabolism , Female , Humans , Induced Pluripotent Stem Cells , Metabolism , Pathology , Male , Models, Biological , Mutation , Neural Stem Cells , Metabolism , Pathology , Xeroderma Pigmentosum , Genetics , Metabolism , Pathology
15.
Indian J Dermatol Venereol Leprol ; 2015 Jan-Fer ; 81 (1): 16-22
Article in English | IMSEAR | ID: sea-154999

ABSTRACT

Background: Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by cutaneous and ocular photosensitivity and an increased risk of developing cutaneous neoplasms. Progressive neurological abnormalities develop in a quarter of XP patients. Aim: To study the clinical profile and perform a mutation analysis in Indian patients with xeroderma pigmentosum. Methods: Ten families with 13 patients with XP were referred to our clinic over 2 years. The genes XPA, XPB and XPC were sequentially analyzed till a pathogenic mutation was identified. Results: Homozygous mutations in the XPA gene were seen in patients with moderate to severe mental retardation (6/10 families) but not in those without neurological features. Two unrelated families with a common family name and belonging to the same community from Maharashtra were found to have an identical mutation in the XPA gene, namely c.335_338delTTATinsCATAAGAAA (p.F112SfsX2). Testing of the XPC gene in two families with four affected children led to the identification of the novel mutations c.1243C>T or p.R415X and c.1677C>A or p.Y559X. In two families, mutations could not be identified in XPA, XPB and XPC genes. Limitation: The sample size is small. Conclusion: Indian patients who have neurological abnormalities associated with XP should be screened for mutations in the XPA gene.


Subject(s)
Adolescent , Adult , Child , Family/epidemiology , Female , Founder Effect , Humans , India/epidemiology , Male , Mutation/analysis , Mutation/genetics , Mutation, Missense/genetics , Neurologic Manifestations , Xeroderma Pigmentosum/epidemiology , Xeroderma Pigmentosum/genetics , Xeroderma Pigmentosum/pathology , Xeroderma Pigmentosum Group A Protein/genetics
16.
São Paulo; s.n; s.n; 2015. 173 p. tab, graf, ilus.
Thesis in Portuguese | LILACS | ID: biblio-847442

ABSTRACT

Espécies reativas de oxigênio (EROs) são normalmente e continuamente geradas em mitocôndrias, majoritariamente na cadeia de transporte de elétrons (CTE). Harman (1956, 1972 e 1992) teorizou que os radicais livres gerados nas mitocôndrias seriam a principal causa do envelhecimento. De fato, durante o envelhecimento é observado um desequilíbrio entre formação e remoção de EROs, que resulta em estresse redox. Essa condição favorece a formação de lesões oxidadas no DNA, acarretando em mutagênese ou morte celular. Diversos mecanismos moleculares cooperam para o reparo de DNA. Duas vias de reparo de DNA lidam com a maioria das lesões: o reparo por excisão de base (BER) e o reparo por excisão de nucleotídeos (NER). A via BER corrige pequenas modificações de bases que surgem de reações de desaminação, alquilação e oxidação. A via NER é mais versátil, reconhecendo lesões que distorcem a dupla hélice de DNA, como danos induzidos por luz UV e adutos volumos. Pacientes xeroderma pigmentoso (XP-A a XP-G) herdam mutações em um de sete genes que codificam proteínas envolvidas na via NER, ou em um gene que codifica uma polimerase translesão (XP-V). A doença é caracterizada por fotosensibilidade e incidência elevada de neoplasias cutâneas. A proteína XPC atua na etapa de reconhecimento da lesão de DNA na subvia de reparo global do genoma (GG-NER), e sua mutação dá origem aos sintomas clássicos de XP. Novas funções de XPC foram recentemente descritas: i) atuando como cofator na via BER auxiliando as DNA glicosilases OGG1, TDG e SMUG; ii) atuando como cofator transcricional de elementos responsivos a Oct4/Sox2, RXR e PPARα; e iii) na adaptação metabólica na transformação de queratinócitos. Então, propusemo-nos a investigar as relações entre XPC e a manutenção da integridade do DNA mitocondrial, a sensibilidade celular a estresse redox mitocondrial e possíveis alterações bioenergéticas e redox. Para tal, padronizamos um ensaio in vitro de cinética de incisão em DNA plasmidial a fim de investigarmos o possível papel de XPC no reparo de lesões oxidadas em mtDNA. Porém, nossos dados revelaram que XPC não se encontra em mitocôndrias. Apesar disso, células XP-C são mais sensíveis ao tratamento com azul de metileno (AM), antimicina A (AA) e rotenona (ROT), que geram estresse redox mitocondrial. A sensibilidade à AA foi completamente revertida em células corrigidas. Células XP-C apresentaram alterações quanto ao uso dos complexos mitocondriais, com diminuição da taxa de consumo de oxigênio (OCR) via complexo I e um aumento da OCR via complexo II, dependente da presença de XPC. Ademais, a linhagem XP-C apresentou um desequilíbrio redox mitocondrial com maior produção de EROs e menor atividade de GPx. O DNA mitocondrial de células XP-C apresentou níveis elevados de lesão e deleção, que no entanto não retornaram aos níveis encontrados em células selvagens na linhagem XP-C corrigida. Observamos uma acentuada diminuição da expressão de PPARGC1A, um importante regulador de biogênese mitocondrial. Contudo, não foi possível determinar o mecanismo de supressão da expressão de PPARGC1A. Por fim, identificamos que o tipo de mutação em XPC pode estar associado a expressão de PPARGC1A. Esse estudo abre novas possibilidade na investigação do papel de proteína XPC, à parte da instabilidade genômica, na adaptação metabólica e desequilíbrio redox em direção da progressão tumoral


Mitochondria continuously produce reactive oxygen species (ROS), mainly at the electron transport chain. Harman (1956, 1972 e 1992) proposed that normal aging is driven by increased mitochondrially generated free radicals. Indeed, during the course of aging there is an increased imbalance between formation and removal of ROS, leading to redox stress. This condition favours the formation of oxidized DNA lesions, given rise to mutations and cell death. Several molecular mechanisms cooperates to repair the DNA. Two DNA repair pathways deal with the majority of lesions: base excision repair (BER) and nucleotide excision repair (NER). The BER pathway corrects small base modifications that arise from deamination, alkylation and oxidation reactions. The NER pathway is more versitile, recognizing helix-distorting lesions, such as UV-induced damage and bulky adducts. Xeroderma pigmentosum (XP-A to XP-G) patients inherit mutations in one of seven protein-coding genes involved in NER pathway, or in a gene coding a translesion DNA polymerase (XP-V). Photosensitivity and a thousand-fold increased in the risk of developing cutaneous neoplasms are the main clinical features of XP. XPC protein functions in the recognition step of global genome NER (GG-NER) sub-pathway, and mutations in this gene lead to classical XP symptoms. Recently, it has been described that XPC acts: i) as a cofactor in BER pathway through functional interaction with DNA glycosylases OGG1, TDG and SMUG1; ii) as coactivator in transcription at Oct4/Sox2, RXR and PPARα responsive elements; iii) in metabolic shift during keratinocytes transformation. Thus, we sought to investigate a possible role for XPC in the maintenance of mtDNA integrity, cellular sensitivity to mitochondrial redox stress and eventual bioenergetic and redox changes. For this purpose, we established an in vitro plasmid incision assay to investigate the possible role of XPC in the repair of oxidized lesions in mitochondrial DNA. However, our data revealed that XPC did not localized in mitochondria. Nonetheless, XP-C cells are more sensitive to methylene blue, antimycin A (AA) and rotenone treatment, which induce mitochondrial redox stress. The XP-C sensitivity to AA was completely reverted in XPC-corrected cells. XP-C cells presented altered usage of mitochondrial complexes, with decreased oxygen consumption rate (OCR) via complex I and increased OCR through complex II, an XPC-dependent phenomenon. Furthermore, the XP-C cell line showed mitochondrial redox imbalance with increased ROS production and decrease GPx activity. MtDNA from XP-C cells accumulate lesions and deletions, which, however, were found at similar levels in the corrected cell line. We identified a sharp decrease in the expression of PPARGC1A, a master regulator of mitochondrial biogenesis. Nevertheless, it was not possible to determine the mechanism of suppression of PPARGC1A expression. Finally, our results suggest a possible link between the type of XPC mutation and PPARGC1A expression. This study unfolds new possible roles for XPC, aside from its established roles in genomic instability, in metabolic adaptation and redox imbalance towards tumour progression


Subject(s)
Electron Transport/genetics , Oxidation-Reduction/drug effects , Cell Line , DNA Damage/genetics , DNA, Mitochondrial/genetics , Fibroblasts , Heat-Shock Proteins/pharmacology , Oxidation-Reduction , Xeroderma Pigmentosum
18.
An. bras. dermatol ; 88(6): 979-981, Nov-Dec/2013. graf
Article in English | LILACS | ID: lil-698984

ABSTRACT

The De Sanctis-Cacchione Syndrome is the rarest and most severe kind of xeroderma pigmentosum, characterized by microcephaly, hypogonadism, neurological disorders, mental and growth retardation, with very few cases published. The clinical findings compatible with De Sanctis-Cacchione Syndrome and the therapeutic approach used to treat a one year and nine months old child, with previous diagnosis of xeroderma pigmentosum, are reported.


A síndrome de de Sanctis-Cacchione é a forma mais rara e grave do xeroderma pigmentoso e é caracterizada por microcefalia, hipogonadismo, alterações neurológicas e retardo mental e de crescimento, com poucos casos publicados. Relatam-se os achados clínicos compatíveis com essa síndrome e a terapêutica instituída em uma lactente de um ano e nove meses, com diagnóstico prévio de xeroderma pigmentoso.


Subject(s)
Female , Humans , Infant , Dwarfism/pathology , Hypogonadism/pathology , Intellectual Disability/pathology , Rare Diseases/pathology , Skin Neoplasms/pathology , Xeroderma Pigmentosum/pathology , Dwarfism/therapy , Hypogonadism/therapy , Intellectual Disability/therapy , Prognosis , Rare Diseases/therapy , Skin Neoplasms/therapy , Skin/pathology , Xeroderma Pigmentosum/therapy
19.
Pakistan Journal of Medical Sciences. 2013; 29 (3): 762-767
in English | IMEMR | ID: emr-127336

ABSTRACT

Polymorphisms in XPG were considered to contribute to the clinical outcome of patients receiving platinum drug chemotherapy. We investigated the impact of several potential SNPs of XPG on the efficacy of platinum-based chemotherapy in NSCLC patients. A total of 433 patients were consecutively selected between Nov. 2006 and Dec. 2007, and were followed-up up to Nov. 2011. The genotyping of six SNPs [rs2296147, rs751402, rs873601, rs4150375, rs17655 and rs2094258] were genotyped using the Taqman real-time PCR method with a 7900 HT sequence detector system. Patients carrying CT+TT genotype of rs2296147 had a significantly longer median PFS [17.5 months] and OS [26.8 months] than CC genotype. Hazard ratio [HR] for PFS and OS in patients with CT+TT genotype of rs2296147 was respectively 0.73[0.51-0.97] and 0.66[0.48-0.99] when compare CC genotype, respectively. Similarly, patients with rs2094258 AG+GG genotype had a longer median progression time [18.4 months] and overall survival time [27.3 months] when compared with those with AA genotype, and HRs[95% CI] for PFS and OS were 0.44[0.34-0.78] and 0.51[0.39-0.82], respectively. Our study suggests rs2296147 CT+TT and rs2094258 AG+GG genotypes contribute to the better survival of NSCLC. Our study provides significant information on role of prognostic value of XPG SNPs, and detecting of XPG could be used as predictive markers toward individualizing NSCLC treatment strategies


Subject(s)
Humans , Female , Male , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms , Xeroderma Pigmentosum , Polymorphism, Single Nucleotide , Survival Rate , Disease-Free Survival , Biomarkers
20.
Pakistan Journal of Medical Sciences. 2013; 29 (3): 823-827
in English | IMEMR | ID: emr-127348

ABSTRACT

We conducted a case-control study by genotyping three potential functional SNPs to assess the association of Xeroderma pigmentosum complementation group F [XPF] polymorphisms with gastric cancer susceptibility, and role of XPF polymorphisms in combination with H.pylori infection in the risk of gastric cancer. A hospital case-control study was conducted. A total of 331 patients with gastric cancer and 355 controls were collected. Three SNPs of XPF, XPF rs180067, rs1799801 and rs2276466, were genotyped by Taqman real-time PCR method with a 7900 HT sequence detector system. The gastric cancer patients were more likely to have smoking habit, a family history of cancer and H.pylori infection. We did not find the significant difference in the genotype distributions of XPF rs180067, rs1799801 and rs2276466 between cases and controls. Multivariate logistic analysis showed a non-significant decreased risk in patients carrying rs180067 G allele, rs1799801 T allele or rs2276466 T allele genotypes. The stratification by H.pylori infection was not significantly different in polymorphisms of XPF rs180067, rs1799801 and rs2276466. There was no evidence that polymorphisms in rs180067, rs1799801 and rs2276466 significantly affect the risk of gastric cancer. Further large sample size studies are strongly needed to validate their association


Subject(s)
Humans , Female , Male , Xeroderma Pigmentosum/genetics , Helicobacter Infections , Stomach Neoplasms/genetics , Stomach Neoplasms/microbiology , Polymorphism, Genetic , Case-Control Studies
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